Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N‐Allylations of N‐Heterocycles

Abstract

Latent nucleophiles are compounds that are themselves not nucleophilic but can produce a strong nucleophile when activated. Such nucleophiles can expand the scope of Lewis base catalyzed reactions. As a proof of concept, we report that N‐silyl pyrroles, indoles, and carbazoles serve as latent N‐centered nucleophiles in substitution reactions of allylic fluorides catalyzed by Lewis bases. The reactions feature broad scopes for both reaction partners, excellent regioselectivities, and produce enantioenriched N‐allyl pyrroles, indoles, and carbazoles when chiral cinchona alkaloid catalysts are used.

Latent (Pro)Nucleophiles in Enantioselective Lewis Base Catalyzed Allylic Substitutions

“…Reflecting the results of the reactions with DABCO, steric and electronic properties of the reaction partners do not hinder the desired N-allylation reactions and focused optimization can be conducted to improve the efficacy of the reactions with specific pairs of reactants. 13 The reactions with chiral Lewis bases are kinetic resolutions of the racemic allylic fluorides and the yields are highest when the fluoride is used in double the stoichiometric quantity. The allylic fluoride remaining at the end of the reactions is enantioenriched.…”

“…Latent nucleophiles are derivatives of nucleophilic molecules that are not markedly nucleophilic but can be activated to act as a nucleophile under specific conditions or with a specific stimulus. 13 These should be distinguished from latent pronucleophiles, which are molecular species that are not nucleophilic in nature but can be transformed into a strong nucleophile by a specific stimulus or a chemical reaction. 14 As a rule, the parent molecule from which the pronucleophile is derived is not (or not markedly) nucleophilic.…”

Enantioselective Catalytic Synthesis of N-alkylated Indoles

“…A new method for the activation of pyrroles, indoles and carbazoles was proposed by Vilotijević et al in 2019 [20]. The silyl-protected indole derivatives 6 can act as latent nucleophiles in the presence of a chiral Lewis base catalyst 4.…”

Palladium and Nickel Catalyzed Suzuki Cross-Coupling with Alkyl Fluorides

“…Significant progress has been reported with substitution, elimination, and cross-coupling reactions using aryl or alkenyl fluorides . Despite emerging reports on carbon–heteroatom bond formation − and carbon–carbon bond construction, − the development of methods that exploit aliphatic substrates still lacks behind C sp2 –F bond functionalization capabilities and is often limited to allylic, propargylic, or benzylic fluorides. − In particular, when highly reactive Lewis acids are required for the carbon–fluorine activation step, the synthetic utility is severely compromised due to low functional group tolerance and competing elimination or rearrangement pathways that result in unsatisfactory yields.…”